Topical preparation for introducing insulin in living organisms

ABSTRACT

The invention relates to topically applicable pharmaceutical preparations which enable one to introduce insulin in living organisms by transdermal resorption. These preparations comprise (i) insulin (ii) capsaicine, histamine and/or cantharis extract, and (iii) an epithelizing agent in admixture with carriers and/or diluents conventionally applicable in topical pharmaceutical preparations, optionally applied onto a support capable of adhering to skin.

The invention relates to topically applicable pharmaceuticalpreparations which enable one to introduce peptidaceous pharmacons inliving organisms by transdermal resorption. The topically applicablepharmaceutical preparations according to the invention may be e.g.ointments, creams, gels, lotions, solutions suspensions and similarformulations routinely utilized in topical treatments. Which can beapplied onto the skin surface optionally in supported forms.Particularly preferred representatives of them are those wherein thetopically applicable formulation is applied onto a support capable ofadhering to skin, i.e. plasters (patches), which enable safe dosing andeasy handling.

Topically applicable pharmaceutical preparations are outstandinglypreferred formulations with respect to the treatment comfort of thepatient. In contrast to parenteral formulations, like injections, theintroduction of which is painful or at least unpleasant and requireseither assistance of a doctor or of a nurse, or, when self-administered,requires practice and skill from the patient, a topical formulation canbe applied to the place of treatment easily and painless even by thepatient. Topical formulations are also more preferred than oral ones forpatients who suffer from dysphagia or are averse to the taste of themedicine. A specific advantage of topical formulations is that thepatient can, either at first sight or by touching his skin, easilyascertain whether he has applied the medicine or not, thereby the riskof inadvertent overdosing or underdosing considerably decreases

Despite of these advantages topically applicable formulations areutilized in medical practice in a rather narrow range, generally onlyfor the treatment of external injuries and local inflammations. Thereasons of this fact lie primarily on the physiological features ofactive agent resorption. In order to enable a topically applied activeagent to reach the target organ in an appropriate concentration theactive agent should penetrate not only through the skin but also throughthe walls of the subdermal blood vessels. Even skin and vessel walls areof highly restricted permeability owing to their physical structures(porosity and semipermeable membrane nature). Further significanthindrance arises from the so-called barrier function of the horny layer,which latter serves essentially to protect living organisms from foreignsubstances contacting the skin.

There have already been elaborated some topical formulations which cansuccessfully replace oral ones for the introduction of the active agentconcerned. One of them is an antirheumatic patch marketed in Hungarysince about 15 years under the name MOTTO^((R)), which comprises formicacid (as an antirheumatic agent) salicylic acid and optionally apain-relieving agent in an emulsion formed with Unguentum emulsificans(a cream comprising nonionic tensides, Ph.Hg.V.), which is applied on asupport capable of adhering to skin. NITRODERM^((R)), a composition soldby Ciba-Geigy Co. (German Federal Republic), comprises nitroglycerol (asa cardiac agent) in a gel formed with methyl or carboxymethyl cellulose,which is applied on small polyurethane sponges capable of adhering toskin. SALONPAS^((R)), a composition sold by Hisamitsu Pharmaceutical Co.Inc. (Japan), comprises methyl salicylate (as an anti-inflammatoryagent) and menthol in a thick mass formed with polyvinyl alcohol, whichis applied on small polyurethane sponges capable of adhering to skin.The active agents in these known compositions are strongly polarsubstances of relatively low molecular weights. thus they have much morechance for resorption than less polar substances with higher molecularweights.

Peptidaceous compounds form an important group of pharmaceuticallyactive substances. In the specification and claims the term“peptidaceous compound” or “peptidaceous pharmacon” refers generally toany pharmaceutically active substance the molecule of which comprises atleast two amino acids bound together by a peptide bond. A narrower groupof them with outstanding pharmaceutical importance is the group ofpolypeptides, of which natural hormones and artificial analogues andderivatives thereof are of particular interest. A member of this lattergroup with outstanding importance from the aspects of public health isinsuline. Hormones and hormone analogues which regulate fine balances ofthe organism are hazardous substances, thus with these substances it isparticularly necessary to decrease the risks of inadvertent overdosingor underdosing. Some representatives of hormones and hormone analogues,in particular insuline, can be introduced only parenterally. Thus itwould be highly desirable to introduce these active agents topically inthe living organism. However, topical preparations applicable forintroducing peptidaceous pharmacons in living organisms have not beendisclosed before.

Based on my studies I have found that, upon utilizing specific auxiliaryagents, peptidaceous pharmacons can be brought to a form capable oftransdermal resorption. This recognition enables one to producetopically applicable pharmaceutical preparations comprising peptidaceouspharmacons

Thus, the invention relates to a topically applicable preparation forintroducing a peptidaceous pharmacon in a living organism. Thepreparation according to the invention comprises

(i) a peptidaceous pharmacon,

(ii) capsaicine, histamine and/or cantharis extract. and

(iii) an epithelizing agent, in admixture with carriers and/or diluentsconventionally applied in topical pharmaceutical preparations,optionally applied onto a support capable of adhering to skin.

The preparations according to the invention may comprise as peptidaceouspharmacon preferably a natural hormone or a synthetic analogue orderivative thereof, particularly preferably insuline. The amounts ofpeptidaceous pharmacons contained in a unit dose (i.e. in a dose for asingle treatment) of the preparations according to the invention (suchas in a single plaster) may be about the same as present in theconventional oral or parenteral unit dose forms. Thus, as an example,plasters according to the invention applicable in the treatment ofdiabetes mellitus may comprise 0.1-50 IU of insuline for one plaster orfor a unit plaster fragment (e.g. for 1 cm² of plaster surface).

Capsaicine, histamine and cantharis extract (the active agent ofTinctura cantharidis), which form component (ii) of the preparationsaccording to the invention, are rubefacient local vasodilators. Thesesubstances have been applied for a long time in the therapy as externalrubs for stimulating subdermal circulation e.g for the treatment ofchilblains, extremital pains, rheuma and the like [Kiráy, Rácz, Török:Bör- és nemibetegsegek (Skin and Venereal Diseases, in Hungarian); 1927and subsequent pages (Medicina Könyvkiadó, Budapest, 1986)]. Asepithelizing agent, which is component (iii) of the preparationaccording to the invention, any agent known to be applied in the therapyto loosen the upper epithelial layer of skin can be utilized.Characteristic representatives of such agents are listed e.g in thetextbook cited above. Salicylic acid, sodium chloride, urea andresorcinol are examples of epithelizing agents which can be utilizedwith good results in the preparations according to the invention.

Although, as it appears from the textbook cited above, components (ii)and (iii) of the preparation according to the invention have alreadybeen utilized before separately in compositions for topical treatment,no data can be found in the literature on their combined use and ontheir prospective combined effects. No data can be found in theliterature, either, that component (ii) or component (iii) would havebeen utilized before in combination with a peptidaceous pharmacon forthe purpose of topical treatments.

In the preparations according to the invention components (i) and (ii)interact with one another, which is verified e.g. by the observationthat when capsaicine is added to an insuline suspension (such as to apreparation sold by Novo Nordisk under the name Insulin lente MC), atransparent solution forms. The accurate nature of this interaction hasnot yet been elucidated, however, most probably hydrogen bonds areformed between the loose hydrogen-bearing groups and the local hydrogenacceptor centres of the two components (such as between the HO-andHOOC-groups of capsaicine and the—NH₂ groups of insuline). In my opinionthe transdermal resorption ability of peptidaceous pharmacons from thepreparations according to the invention can be attributed basically tothis interaction.

The preparations according to the invention must contain component (ii)at least in an amount enabling the above interaction to take place, itis preferred, however, when the preparations contain more component (ii)than this minimum. For any individual peptidaceous pharmacon/component(ii) pairs the minimum and suitable ratios can be determined easily bytests belonging to the routine knowledge of one skilled inpharmacotechnology. As a guidance, e.g. insuline-containing preparationsaccording to the invention may contain 0.001-0.3 a, preferably 0.003-0.1g, particularly preferably 0.005-0.05 g of component (ii) for 10 IU ofinsuline

The preparations according to the invention may contain components (ii)and (iii) in a weight ratio of 1:(0.01-10), preferably in a weight ratioof 1:(0.03-3), particularly preferably in a weight ratio of 1:(0.05-2).

I have observed that the higher is the amount of components (ii) and(iii) in the preparation according to the invention, the faster is theresorption of the active agent.

The preparations according to the invention comprise components(i)-(iii) in admixture with conventional carriers and/or diluents fortopical preparations, of which the following are listed as examples:water, alcohols (also comprising glycerol), glycols, gellifying agents(such as methyl cellulose, carboxymethyl cellulose, polyvinyl alcoholand polyvinyl acetate), ointment bases (such as lanoline), ionic andmonionic tenzides and the like.

The preparations according to the invention may also comprise thepeptidaceous pharmacon in enveloped form (such as closed into a cyclicstarch or microencapsulated). Use of such an envelope may be necessaryfrom pharmacotechnological considerations, for instance when thepeptidaceous pharmacon concerned is incompatible with the selectedcarriers or diluents. For instance, hydrophilic pharmacons, when closedinto an envelope of hydrophobic surface, can be rendered compatible withoily carriers. In such instances the interaction between components (i)and (ii) proceeds at the rate of liberation of component (i) from theenvelope.

If desired, the preparations according to the invention may alsocomprise other pharmaceutically active or activity-increasing agents tobe introduced together with the peptidaceous pharmacon. Examples of suchcomponents are zinc compounds which are sometimes added together withinsuline.

If desired, the preparations according to the invention may alsocomprise an indicator suitable to detect the presence of thepeptidaceous pharmacon. Substances which react with a visuallyobservable change (most suitably with a colour reaction) to the presenceor absence of the pharmacon concerned can be utilized as indicators.Ninhydrine, which indicates the presence of a peptidaceous substance byblue colouration, is a very suitable indicator to show the presence ofpeptidaceous substances. A great advantage of such indicator-containingpreparations is that the patient can easily conclude from the colourchange of the applied composition (e.g. from the disappearance of theblue colour of ninhydrine) whether resorption has taken place or not,and, if necessary, can change the already exhausted plasters at dueintervals. The preparations according to the invention may comprise theindicator in amounts which provide good observability. These amounts arewell known to one skilled in analytics or can be determined easily byroutine tests.

The following examples serve to demonstrate the composition andmanufacture of the preparations according to the invention.

EXAMPLE 1

0.28 ml of Tinctura capsaicini (Ph. Hg. V. capsaicine-containing 70%alcohol solution) and 0.05 g of salicylic acid were added to 10 ml of anintramuscularly administerable aqueous suspension comprising 40 lU/mi ofinsuline (sold by Novo Nordisk under the trade name Insulin rapitard).Upon adding the capsaicine, a transparent solution formed from theinsuline suspension. 0.01% by weight of ninhydrine were added to thesolution, whereupon the colour of the solution turned blue. Theresulting solution was gellified by adding 15% by weight of methylcellulose, and the resulting gel was applied onto a polyurethane spongeplaster with an active surface of 20 cm². The gel applied was coveredwith aluminium foil.

EXAMPLE 2

10 g of Unguentum nonionicum emulsificans (Ph.Hg.V., an oily gel formedwith nonionic tenzides) was admixed with 10 g (400 IU) of crystallineinsuline, 0.05 g of crystalline salicylic acid and 0.28 ml of Tincturacapsaicini. The resulting oily ointment was applied onto a polyurethanesponge plaster with an active sur-face of 20 cm² and the ointmentapplied was covered with aluminium foil.

I claim:
 1. A topically applicable preparation for introducing insulinin a living organism, which comprises: (i) insulin, (ii) a memberselected from the group consisting of capsaicine, histamine andcantharis extract, and (iii) an epthelizing agent which loosens theupper epithelial layer of skin in admixture with a topicallypharmaceutically acceptable excipient, component (ii) being present inan amount of 0.001-0.3 g for 10 IU of said insulin which, when added toan aqueous suspension of component (i), forms a solution.
 2. Apreparation as claimed in claim 1, which comprises 0.003-0.1 g ofcomponent (ii) for 10 IU of said pharmacon.
 3. A preparation as claimedin claim 2, which comprises 0.005-0.05 g of component (ii) for 10 IU ofsaid pharmacon.
 4. A preparation as claimed in claim 1, which comprisescomponents (ii) and (iii) in a weight ratio of 1:(0.01-10).
 5. Apreparation as claimed in claim 4, which comprises components (ii) and(iii) in a weight ratio of 1:(0.03-3).
 6. A preparation as claimed inclaim 5, which comprises components (ii) and (iii) in a weight ratio of1:(0.05-2).
 7. A preparation as claimed in claim 1, which furthercomprises an indicator which reacts to the presence or absence of saidpharmacon by a visually observable change.
 8. A preparation as claimedin claim 7, wherein said indicator is ninhydrine.